Diabetes-induced changes in retinal vascular permeability (blood-retinal barrier dysfunction) are a major contributor to macular edema, the most common cause of visual loss in diabetic retinopathy. Anti-VEGF therapies have emerged as an approach to preserve or even improve visual function. However, this treatment is only partially effective and not all individuals respond. Evidence suggests that multiple other factors contribute to blood-retinal barrier dysfunction, including tumor necrosis factor and the chemokine (C-C motif) ligand 2 (CCL2). It is therefore essential to gain additional insights to allow the development of new therapeutic strategies. In the search for new treatments, there is increasing appreciation for the importance of protective mechanisms which could counteract key pathogenic processes, with the idea that enhancing these protective mechanisms could delay the progression of diabetic retinopathy. An additional important theme in the field is the growing understanding of the contribution of diverse cell types to diabetic retinopathy, including and in addition to vascular endothelial cells. During the previous funding period we identified Nrf2 as an important protective mechanism in diabetic retinopathy and other retinal conditions, impacting on diverse processes including blood-retinal barrier dysfunction and retinal neuronal dysfunction. An important basis for its action is that Nrf2 counteracts oxidative stress and regulates the cytokine environment in the retina. We also found that pharmacologic activation of Nrf2 is protective in retinal vascular disease processes, with multiple beneficial endpoints including neuroprotection. Taken together, this suggests to us that Nrf2 is a promising candidate for therapeutic modulation in DR, especially in light of emerging evidence that diabetes can impair Nrf2 activity in the retina. Here we propose to investigate the molecular basis for Nrf2's protective effect as well as to determine the cellular context for Nrf2 action in diabetic retinopathy. In addition, we will investigate a promising Nrf2 activator for treatment of blood-retinal barrier dysfunction in diabetic retinopathy. These studies will provide new insights into the mechanisms for Nrf2's beneficial effects as well as provide insights into the specific cell types in which Nrf2 function is particularly critical. Validation of pharmacologic targeting of Nrf for amelioration of pathologic endpoints could lead to direct clinical translation and implicate Nrf2 as a new therapeutic target for diabetic macular edema.